Method of enhancing absorption of ingested medicaments for treatment of parkinsonism

ABSTRACT

A method of using a vibrating gastrointestinal capsule in coordination with an ingestible medicament for treatment of Parkinsonism. The vibrating gastrointestinal capsule, is provided to the subject, and includes: a housing; a vibrating agitation mechanism causing said housing to exert vibrations on an environment surrounding the vibrating gastrointestinal capsule; a power supply for powering said vibrating agitation mechanism; and a control mechanism for activating said vibrating agitation mechanism to operate in said vibration mode of operation. The subject ingests the ingestible medicament and the vibrating gastrointestinal capsule. At least one of a time of ingesting of the vibrating gastrointestinal capsule and a timing or activation delay of the vibration mode of operation is controlled, such that the vibration mode of operation at least partially transpires or completely transpires within an actual or estimated absorption time period of the ingestible medicament within the gastrointestinal tract of the subject.

FIELD OF THE INVENTION

The present invention relates in general to vibrating capsule systemsincluding one or more vibrating capsules, and to treatment methods usingsuch systems and capsules, and more particularly, to vibrating capsulesystems and methods for enhancing the absorption to the blood stream ofan ingested medicament for treatment of Parkinsonism.

SUMMARY OF THE INVENTION

In accordance with an embodiment of the present invention, there isprovided a vibrating ingestible capsule for promoting absorption of aningested medicament into the blood stream, the vibrating ingestiblecapsule including:

a housing;

a vibrating agitation mechanism adapted such that, in a vibration modeof operation, the housing exerts vibrations on an environmentsurrounding the vibrating gastrointestinal capsule;

a power supply disposed within the housing and adapted to power thevibrating agitation mechanism; and

a control mechanism adapted to activate the vibrating agitationmechanism to be operative in the vibration mode of operation, thecontrol mechanism adapted to control a timing or activation delay of thevibration mode of operation such that the vibration mode of operation atleast partially transpires within at least one of an estimatedabsorption time period and an actual absorption time period of theingested medicament within the gastrointestinal tract of the subject.

In some embodiments, the control mechanism is adapted to activate thevibration agitation mechanism to be operative in the vibration mode ofoperation in response to receipt of an activation input.

In some embodiments, the vibrating ingestible capsule further includesat least one sensor adapted to provide the activation input.

In some embodiments, the at least one sensor includes an illuminationsensor, and the receiving the at least one activation input includesreceiving input indicating transition of the capsule from an illuminatedenvironment to a dark environment.

In some embodiments, the at least one sensor includes a pressure sensorand the receiving the at least one activation input includes receivinginput indicting pressure applied to the capsule, which pressure isindicative of the capsule moving through a pharynx of the subject.

In some embodiments, the at least one sensor includes a temperaturesensor, and the receiving the at least one activation input includesreceiving input indicating transition of the capsule from an area withambient temperature to an area with a human body temperature.

In some embodiments, the at least one sensor includes an accelerometer,and the receiving the at least one activation input includes receivingthe activation input in response to a detected activation motion carriedout with the gastrointestinal capsule.

In some embodiments, the at least one sensor includes a moisture sensor,and the receiving the at least one activation input includes receivinginput indicating transition of the capsule from a dry environment to ahumid environment.

In some embodiments, the vibrating ingestible capsule is functionallyassociated with a control unit remote from the vibrating ingestiblecapsule, and the control mechanism is adapted to receive the activationinput from the control unit remote.

In some embodiments, the control mechanism is adapted to receive theactivation input following ingesting of the vibrating capsule.

In some embodiments, the control mechanism is adapted to receive theactivation input prior to ingesting of the vibrating capsule.

In some embodiments, the control mechanism is adapted to receive theactivation input by receiving a vibration protocol to be used by thecontrol mechanism to control operation of the vibrating agitationmechanism.

In some embodiments, the vibrating agitation mechanism includes at leasta radial agitation mechanism adapted, in the vibration mode ofoperation, to exert radial forces on the housing, in a radial directionwith respect to a or the longitudinal axis of the housing, thereby tocause the vibrations exerted by the housing.

In some embodiments, the vibrating agitation mechanism includes at leastan axial agitation mechanism adapted, in the vibration mode ofoperation, to exert axial forces on the housing, in an axial directionwith respect to a or the longitudinal axis of the housing, thereby tocause the vibrations exerted by the housing.

In some embodiments, the vibrating agitation mechanism includes a radialagitation mechanism adapted to exert the radial forces and a separateaxial agitation mechanism adapted to exert the axial forces.

In some embodiments, the vibrating agitation mechanism includes a singleagitation mechanism adapted to exert the radial forces and the axialforces.

In some embodiments, the control mechanism is adapted to control thevibrating agitation mechanism such that the vibrating mode of operationincludes a plurality of cycles, each of the cycles including a vibrationduration followed by a repose duration, wherein the housing exerts thevibrations during the vibration duration.

In some embodiments, the repose duration is greater than the vibrationduration.

In some embodiments, the vibration duration is in the range of 0.1second to 10 seconds, 1 second to 10 seconds, 1 second to 9 seconds, 2seconds to 9 seconds, 3 seconds to 9 seconds, 3 seconds to 8 seconds, 3seconds to 7 seconds, 3 seconds to 6 seconds, 4 seconds to 6 seconds, or5 seconds to 6 seconds.

In some embodiments, the repose duration is in the range of 1 second to180 seconds, 3 seconds to 180 seconds, 5 seconds to 180 seconds, 5seconds to 150 seconds, 5 seconds to 120 seconds, 8 seconds to 100seconds, 8 seconds to 30 seconds, 10 seconds to 80 seconds, 10 secondsto 70 seconds, 10 seconds to 60 seconds, 10 seconds to 50 seconds, 10seconds to 40 seconds, 10 seconds to 30 seconds, 10 seconds to 20seconds, or 15 seconds to 20 seconds.

In some embodiments, a duration of each of the plurality of cycles is inthe range of 1.1 seconds to 200 seconds, 5 seconds to 200 seconds, 10seconds to 200 seconds, 10 seconds to 150 seconds, 10 seconds to 100seconds, 10 seconds to 80 seconds, 10 seconds to 50 seconds, 10 secondsto 40 seconds, 10 seconds to 30 seconds, 15 seconds to 50 seconds, 15seconds to 40 seconds, 15 seconds to 30 seconds, or 15 seconds to 25seconds.

In some embodiments, the control mechanism is adapted to control thevibrating agitation mechanism such that a cumulative duration of thevibrating mode of operation is in the range of 1 hour to 12 hours, 2hours to 10 hours, 2 hours to 8 hours, 2 hours to 6 hours, 2 hours to 4hours, or 2 hours to 3 hours.

In some embodiments, in the first vibration mode of operation, thevibrating agitation mechanism is configured such that a net forceexerted by the housing on the environment is in the range of 50grams-force to 600 grams-force.

In some embodiments, in the first vibration mode of operation thevibrating agitation mechanism is configured to exert the forces on thehousing to attain a vibrational frequency within a range of 10 Hz to 650Hz, 15 Hz to 600 Hz, 20 Hz to 550 Hz, 30 Hz to 550 Hz, 50 Hz to 500 Hz,70 Hz to 500 Hz, 100 Hz to 500 Hz, 130 Hz to 500 Hz, or 150 Hz to 500Hz.

In accordance with another embodiment of the present invention, there isprovided a method of using a vibrating gastrointestinal capsule incoordination with an ingestible medicament for treatment ofParkinsonism, the method including:

(a) providing the vibrating gastrointestinal capsule, the capsuleincluding:

-   -   a housing;    -   a vibrating agitation mechanism adapted such that, in a        vibration mode of operation, the housing exerts vibrations on an        environment surrounding the vibrating gastrointestinal capsule;    -   a power supply disposed within the housing and adapted to power        the vibrating agitation mechanism; and    -   a control mechanism adapted to activate the vibrating agitation        mechanism to operate in the vibration mode of operation;        (b) ingesting the ingestible medicament;        (c) ingesting the vibrating gastrointestinal capsule; and        (d) controlling at least one of a time of the ingesting of the        vibrating gastrointestinal capsule and a timing or activation        delay of the vibration mode of operation, such that the        vibration mode of operation at least partially transpires within        at least one of an estimated absorption time period and an        actual absorption time period of the ingestible medicament        within the gastrointestinal tract of the subject.

In some embodiments, the controlling is effected such that the vibrationmode of operation at least partially transpires during the actualabsorption time.

In some embodiments, the actual absorption time period occurs when theingestible medicament is disposed in a stomach of the subject. In someembodiments, the actual absorption time period occurs when theingestible medicament is disposed in a small intestine of the subject.In some embodiments, the actual absorption time period occurs when theingestible medicament is disposed in a large intestine of the subject.

In some embodiments, the controlling of is effected such that thevibration mode of operation at least partially transpires during theestimated absorption time. In some embodiments, the estimated absorptiontime is within a range of 0.5 to 1.5 hours. In some embodiments, theestimated absorption time is within a range of 1.0 to 5 hours. In someembodiments, the estimated absorption time is within a range of 0.5 to 5hours. In some embodiments, the estimated absorption time is within arange of 4 to 30 hours.

In some embodiments, the ingesting of the vibrating gastrointestinalcapsule transpires within 4 hours, within 3.5 hours, within 3 hours,within 2.5 hours, within 2 hours, within 1.5 hours, within 1 hour, orwithin 0.5 hours of, or after, the ingesting of the ingestiblemedicament.

In some embodiments, the ingesting of the vibrating gastrointestinalcapsule is simultaneous with the ingesting of the ingestible medicament.

In some embodiments, the method further includes timing the vibrationmode of operation to at least partially transpire within 5 hours, within4 hours, within 3.5 hours, within 3 hours, within 2.5 hours, within 2hours, within 1.5 hours, within 1 hour, or within 0.5 hours of theingesting of the ingestible medicament.

In some embodiments, the ingestible medicament is at least partiallyabsorbable in a stomach of a subject or in the stomach of the subject.In some embodiments, the ingestible medicament is at least partiallyabsorbable in a small intestine of a subject or in the small intestineof the subject.

In some embodiments, the ingestible medicament for treatment ofParkinsonism includes levodopa. In some embodiments, the ingestiblemedicament for treatment of Parkinsonism includes at least onedopaminergic agent. In some embodiments, the ingestible medicament fortreatment of Parkinsonism includes at least one catecholamine precursor.In some embodiments, the at least one catecholamine precursor includes adopamine precursor. In some such embodiments, the dopamine precursorincludes at least one dopamine precursor agent such as(L)-3,4-dihydroxyphenylalanine. In some embodiments, the ingestiblemedicament for treatment of Parkinsonism includesN-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine. In someembodiments, the ingestible medicament for treatment of Parkinsonismincludes tyrosine hydroxylase. In some embodiments, the ingestiblemedicament for treatment of Parkinsonism includes apomorphine. In someembodiments, the ingestible medicament for treatment of Parkinsonismincludes at least one anticholinergic agent. In some embodiments, theingestible medicament for treatment of Parkinsonism includes at leastone agent selected to antagonize at least one cholinergic receptor. Insome embodiments, the ingestible medicament for treatment ofParkinsonism includes at least one of benzhexol and orphenadrine. Insome embodiments, the ingestible medicament for treatment ofParkinsonism includes at least one selective allosteric potentiator ofmetabotropic glutamate receptor 4 (mGluR4), optionallyN-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide.

In some embodiments, the medicament for treatment of Parkinsonism isadapted to delay an onset of Parkinsonism. In some embodiments, themedicament for treatment of Parkinsonism is adapted to mitigate orretard a development of Parkinsonism. In some embodiments, themedicament for treatment of Parkinsonism is adapted to manage acondition of Parkinsonism.

In some embodiments, the vibration mode of operation at least partiallytranspiring within at least one of an estimated absorption time periodand an actual absorption time period of the ingestible medicament withinthe gastrointestinal tract of the subject the effects an increasedabsorption of the ingestible medicament for treatment of Parkinsonism,thereby improving a therapeutic efficacy of the medicament.

In some embodiments, the vibration mode of operation at least partiallytranspiring within at least one of an estimated absorption time periodand an actual absorption time period of the ingestible medicament withinthe gastrointestinal tract of the subject effects an increasedabsorption of the ingestible medicament for treatment of Parkinsonism,thereby enabling the use of a lower dosage of the medicament, optionallywithout impairing or diminishing therapeutic efficacy.

In some embodiments, the vibration mode of operation is effected withinthe gastrointestinal tract so as to stimulate the enteric nervous systemof the subject. In some embodiments, the vibration mode of operation iseffected within the gastrointestinal tract so as to induce at least oneperistaltic wave in a wall of the gastrointestinal tract. In someembodiments, the vibration mode of operation is effected within thegastrointestinal tract so as to effect increasing peristalsis in a wallof the gastrointestinal tract. In some embodiments, increasingperistalsis is effected so as to stimulate the enteric nervous system ofthe subject.

In some embodiments, the vibrating gastrointestinal capsule is adaptedand/or dimensioned to transit the gastrointestinal tract of the subjector of a subject.

In some embodiments, the capsule further includes a control mechanismadapted, in response to receipt of an activation input, to activate thevibrating agitation mechanism to operate in the vibration mode ofoperation.

In some embodiments, the capsule further includes at least one sensoradapted to provide the activation input.

In some embodiments, the at least one sensor includes an illuminationsensor, and the receiving the at least one activation input includesreceiving input indicating transition of the capsule from an illuminatedenvironment to a dark environment.

In some embodiments, the at least one sensor includes a pressure sensorand the receiving the at least one activation input includes receivinginput indicting pressure applied to the capsule, which pressure isindicative of the capsule moving through a pharynx of the subject.

In some embodiments, the at least one sensor includes a temperaturesensor, and the receiving the at least one activation input includesreceiving input indicating transition of the capsule from an area withambient temperature to an area with a human body temperature.

In some embodiments, the at least one sensor includes an accelerometer,and the receiving the at least one activation input includes receivingthe activation input in response to a detected activation motion carriedout with the gastrointestinal capsule.

In some embodiments, the at least one sensor includes a moisture sensor,and the receiving the at least one activation input includes receivinginput indicating transition of the capsule from a dry environment to ahumid environment.

In some embodiments, the receipt of the activation input includesreceiving the activation input from a control unit remote from thegastrointestinal capsule. In some embodiments, receiving the activationinput includes receiving the activation input following the ingesting.In some embodiments, receiving the activation input includes receivingthe activation input prior to the ingesting. In some embodiments,receiving the activation input additionally includes receiving avibration protocol to be used by the control mechanism to controloperation of the vibrating agitation mechanism.

In some embodiments, the vibrating agitation mechanism includes at leasta radial agitation mechanism, and the controlling includes controllingthe radial agitation mechanism, in the vibration mode of operation, toexert radial forces on the housing, in a radial direction with respectto a or the longitudinal axis of the housing, thereby to cause thevibrations exerted by the housing.

In some embodiments, the vibrating agitation mechanism includes at leastan axial agitation mechanism, and wherein the control mechanism isadapted to control the axial agitation mechanism, in the vibration modeof operation, to exert axial forces on the housing, in an axialdirection with respect to a or the longitudinal axis of the housing,thereby to cause the vibrations exerted by the housing.

In some embodiments, the control mechanism is adapted to control thevibrating agitation mechanism, in the vibration mode of operation, toexert radial forces on the housing in a radial direction with respect toa or the longitudinal axis of the housing and to exert axial forces onthe housing in an axial direction with respect to a or the longitudinalaxis of the housing, thereby to cause the vibrations exerted by thehousing.

In some embodiments, the vibrating agitation mechanism includes a radialagitation mechanism adapted to exert the radial forces and a separateaxial agitation mechanism adapted to exert the axial forces.

In some embodiments, the vibrating agitation mechanism includes a singleagitation mechanism adapted to exert the radial forces and the axialforces.

In some embodiments, the control mechanism is adapted to control thevibrating agitation mechanism such that the vibrating mode of operationincludes a plurality of cycles, each of the cycles including a vibrationduration followed by a repose duration, wherein the housing exerts thevibrations during the vibration duration.

In some embodiments, the repose duration is greater than the vibrationduration.

In some embodiments, the vibration duration is in the range of 0.1second to 10 seconds, 1 second to 10 seconds, 1 second to 9 seconds, 2seconds to 9 seconds, 3 seconds to 9 seconds, 3 seconds to 8 seconds, 3seconds to 7 seconds, 3 seconds to 6 seconds, 4 seconds to 6 seconds, or5 seconds to 6 seconds.

In some embodiments, the repose duration is in the range of 1 second to180 seconds, 3 seconds to 180 seconds, 5 seconds to 180 seconds, 5seconds to 150 seconds, 5 seconds to 120 seconds, 8 seconds to 100seconds, 8 seconds to 30 seconds, 10 seconds to 80 seconds, 10 secondsto 70 seconds, 10 seconds to 60 seconds, 10 seconds to 50 seconds, 10seconds to 40 seconds, 10 seconds to 30 seconds, 10 seconds to 20seconds, or 15 seconds to 20 seconds.

In some embodiments, a duration of each of the plurality of cycles is inthe range of 1.1 seconds to 200 seconds, 5 seconds to 200 seconds, 10seconds to 200 seconds, 10 seconds to 150 seconds, 10 seconds to 100seconds, 10 seconds to 80 seconds, 10 seconds to 50 seconds, 10 secondsto 40 seconds, 10 seconds to 30 seconds, 15 seconds to 50 seconds, 15seconds to 40 seconds, 15 seconds to 30 seconds, or 15 seconds to 25seconds.

In some embodiments, the control mechanism is adapted to control thevibrating agitation mechanism such that a cumulative duration of thevibrating mode of operation is in the range of 1 hour to 12 hours, 2hours to 10 hours, 2 hours to 8 hours, 2 hours to 6 hours, 2 hours to 4hours, or 2 hours to 3 hours.

In some embodiments, in the first vibration mode of operation, thevibrating agitation mechanism is configured such that a net forceexerted by the housing on the environment is in the range of 50grams-force to 600 grams-force.

In some embodiments, in the first vibration mode of operation thevibrating agitation mechanism is configured to exert the forces on thehousing to attain a vibrational frequency within a range of 10 Hz to 650Hz, 15 Hz to 600 Hz, 20 Hz to 550 Hz, 30 Hz to 550 Hz, 50 Hz to 500 Hz,70 Hz to 500 Hz, 100 Hz to 500 Hz, 130 Hz to 500 Hz, or 150 Hz to 500Hz.

In accordance with a further embodiment of the present invention, thereis provided a method of using a vibrating gastrointestinal capsule incoordination with an ingestible medicament for treatment ofParkinsonism, the method including:

(a) providing the vibrating gastrointestinal capsule, the capsuleincluding:

-   -   a housing;    -   a vibrating agitation mechanism adapted such that, in a        vibration mode of operation, the housing exerts vibrations on an        environment surrounding the vibrating gastrointestinal capsule;    -   a power supply disposed within the housing and adapted to power        the vibrating agitation mechanism; and    -   a control mechanism adapted to activate the vibrating agitation        mechanism to operate in the vibration mode of operation;        (b) ingesting the vibrating gastrointestinal capsule;        (c) ingesting the ingestible medicament; and        (d) controlling at least one of a time of ingesting the        vibrating gastrointestinal capsule and a timing of the vibration        mode of operation such that the vibration mode at least        partially transpires within a particular time period with        respect to the ingesting of the ingestible medicament.

In some embodiments, the particular time period is within 5 hours,within 4 hours, within 3.5 hours, within 3 hours, within 2.5 hours,within 2 hours, within 1.5 hours, within 1 hour, or within 0.5 hours ofthe ingesting of the ingestible medicament.

In some embodiments, controlling includes both controlling the time ofingesting the vibrating gastrointestinal capsule and the timing of thevibration mode of operation.

In some embodiments, controlling is effected so as to improve absorptionof the ingestible medicament within a gastrointestinal tract of asubject.

In accordance with another embodiment of the present invention, there isprovided a method of using a vibrating gastrointestinal capsule incoordination with an ingestible medicament for treatment ofParkinsonism, the method including:

(a) providing the vibrating gastrointestinal capsule, the capsuleincluding:

-   -   a housing;    -   a vibrating agitation mechanism adapted such that, in a        vibration mode of operation, the housing exerts vibrations on an        environment surrounding the vibrating gastrointestinal capsule;    -   a power supply disposed within the housing and adapted to power        the vibrating agitation mechanism; and    -   a control mechanism adapted to activate the vibrating agitation        mechanism to operate in the vibration mode of operation;        (b) ingesting the ingestible medicament;        (c) ingesting the vibrating gastrointestinal capsule; and        (d) controlling at least one of a time of the ingesting of the        vibrating gastrointestinal capsule and a timing or activation        delay of the vibration mode of operation, such that the        vibration mode of operation at least partially transpires within        an estimated absorption time period of the ingestible medicament        within the gastrointestinal tract of the subject. In accordance        with a further embodiment of the present invention, there is        provided a method of using a vibrating gastrointestinal capsule        in coordination with an ingestible medicament for treatment of        Parkinsonism, the method including:        (a) providing the vibrating gastrointestinal capsule, the        capsule including:    -   a housing;    -   a vibrating agitation mechanism adapted such that, in a        vibration mode of operation, the housing exerts vibrations on an        environment surrounding the vibrating gastrointestinal capsule;    -   a power supply disposed within the housing and adapted to power        the vibrating agitation mechanism; and    -   a control mechanism adapted to activate the vibrating agitation        mechanism to operate in the vibration mode of operation;        (b) ingesting the ingestible medicament;        (c) ingesting the vibrating gastrointestinal capsule; and        (d) controlling at least one of a time of the ingesting of the        vibrating gastrointestinal capsule and a timing or activation        delay of the vibration mode of operation, such that the        vibration mode of operation at least partially transpires within        an actual absorption time period of the ingestible medicament        within the gastrointestinal tract of the subject.

In accordance with yet another embodiment of the present invention,there is provided a kit for promoting absorption of an ingestedmedicament into the blood stream, the kit including:

a medicament to be ingested; and

vibrating ingestible capsule including:

-   -   a vibrating agitation mechanism adapted such that, in a        vibration mode of operation, the housing exerts vibrations on an        environment surrounding the vibrating gastrointestinal capsule;    -   a power supply disposed within the housing and adapted to power        the vibrating agitation mechanism; and    -   a control mechanism adapted to activate the vibrating agitation        mechanism to operative in the vibration mode of operation, the        control mechanism adapted to control a timing or activation        delay of the vibration mode of operation such that the vibration        mode of operation at least partially transpires within at least        one of an estimated absorption time period and an actual        absorption time period of the ingested medicament within the        gastrointestinal tract of the subject.

In accordance with a further embodiment of the present invention, thereis provided use of a vibrating ingestible capsule for promotingabsorption of an ingested medicament into the blood stream, thevibrating ingestible capsule including:

a housing;

a vibrating agitation mechanism adapted such that, in a vibration modeof operation, the housing exerts vibrations on an environmentsurrounding the vibrating gastrointestinal capsule;

a power supply disposed within the housing and adapted to power thevibrating agitation mechanism; and

a control mechanism adapted to activate the vibrating agitationmechanism to operative in the vibration mode of operation, the controlmechanism adapted to control a timing or activation delay of thevibration mode of operation such that the vibration mode of operation atleast partially transpires within at least one of an estimatedabsorption time period and an actual absorption time period of theingested medicament within the gastrointestinal tract of the subject.

BRIEF DESCRIPTION OF THE FIGURES

The foregoing discussion will be understood more readily from thefollowing detailed description of the invention, when taken inconjunction with the accompanying FIGS. 1-2), in which:

FIG. 1 is a schematic block diagram of a gastrointestinal treatmentsystem including a vibrating ingestible capsule according to anembodiment of the present invention; and

FIG. 2 is a schematic flowchart of a method for using a vibratinggastrointestinal capsule to improve or accelerate the absorption to theblood stream of an ingestible medicament for treatment of Parkinsonism,or to improve the efficacy of such a medicament, according to thepresent invention, the method being based on use of an ingestiblevibrating gastrointestinal capsule, for example as shown in FIG. 1.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The principles of the inventive gastrointestinal treatment system andmethod of enhancing the absorption into the bloodstream of ingestiblemedicaments for treating Parkinsonism using the inventivegastrointestinal treatment system, may be better understood withreference to the drawings and the accompanying description.

Before explaining at least one embodiment of the invention in detail, itis to be understood that the invention is not limited in its applicationto the details of construction and the arrangement of the components setforth in the following description or illustrated in the drawings. Theinvention is capable of other embodiments or of being practiced orcarried out in various ways. Also, it is to be understood that thephraseology and terminology employed herein is for the purpose ofdescription and should not be regarded as limiting.

For the purposes of this application, the term “subject” relates to ahuman.

For the purposes of this application, the term “vibrating ingestiblecapsule” relates to an ingestible capsule adapted to at leastintermittently vibrate, for a cumulative duration of at least oneminute, in accordance with a vibration protocol of the capsule.

For the purposes of this application, the term “vibrating agitationmechanism” refers to any type of mechanism that vibrates or causeselements in its vicinity to vibrate, including a vibration motor orengine and a pendulum.

For the purposes of this application, the term “intermittently activatedvibrating agitation mechanism” refers to a vibration agitation mechanismthat vibrates or causes elements in its vicinity to vibrate and isoperative at certain times, and does not vibrate or cause elements inits vicinity to vibrate at other times, the activation times beingselected by a control mechanism or other control unit controlling thevibration agitation mechanism.

For the purposes of this application, the term “vibration protocol”relates to a protocol specifying vibration parameters of anintermittently activated vibrating agitation mechanism of a vibratingingestible capsule. Typically, the vibration protocol relates to anactivation delay for initiating vibration (e.g., a duration between“initial” activation of the capsule and the first activation of thevibration agitation mechanism), a vibration rate (number of vibrationcycles per hour), a vibration duration and a repose duration for eachvibration cycle, a vibration frequency, an amount of force exerted bythe vibrations, and the like.

For the purposes of this application, the term “treatment procedure”relates to parameters of a treatment utilizing vibrating ingestiblecapsules, which are typically defined by a treating physician or medicalpractitioner. For example, the treatment procedure may include thenumber of capsules to be taken within a specific time duration (e.g., 3capsules per week, 2 capsules per day), the frequency at which capsulesshould be taken, the time of day at which capsules should be taken,whether the capsule should be taken with or without food, and the like.

For the purpose of this application, the term “treatment protocol”relates to all aspects of treatment of a subject with a vibratingingestible capsule, and includes the treatment procedure as well as thevibration protocol to be used for treating the subject.

For the purpose of this application, the term “activation input” relatesto an input received by a control mechanism or control mechanism of avibrating ingestible capsule, which causes the control mechanism orcontrol mechanism of the capsule to activate itself, so as to be able toprocess inputs and/or to control additional components of the capsule.The activation input may be received from an element forming part of thecapsule, such as a sensor sensing specific conditions in which thecapsule should be activated, or from a remote source, such as a remotecontrol mechanism, for example by way of a signal transmitted to thecapsule, magnetic field applied to the capsule, specific motion appliedto the capsule, or any other type of input provided to the capsule froma remote source.

For the purpose of this application, a vibrating ingestible capsule issaid to be in an “inoperative state” when the capsule is in a storagecondition, intended to preserve the life of a battery thereof. In theinoperative state, components of the capsule which are intended toreceive or to provide an activation input, such as specific sensors,transceivers, and/or timing mechanisms may be active at least to aminimal degree. However, in the inoperative state, no vibration takesplace, and a control mechanism controlling vibration of the capsule isinactive.

For the purpose of this application, a vibrating ingestible capsule issaid to be in an “operative state” when the control mechanism of thecapsule is processing inputs and data, and can cause a vibratingagitation mechanism of the capsule to vibrate or cause elements in itsvicinity to vibrate.

For the purpose of this application, an “ingestible medicament” is atleast partially absorbable to the bloodstream from within the stomach,small intestine, and large intestine, and more typically, within thestomach or small intestine.

For the purpose of this application, the term “partially absorbable” ismeant to include the possibility that the environment within thegastrointestinal tract (including acids, enzymes, etc. thereof) maychemically modify the ingested medicament in order to achieve thecharacteristic “partially absorbable”.

For the purpose of this application, an estimated absorption time may bedetermined as follows:

(i) ingestible medicaments that are absorbed in the stomach have anestimated absorption time within a range of 0.5 to 1.5 hours from thetime of ingestion of the medicament;

(ii) ingestible medicaments that are absorbed in the small intestinehave an estimated absorption time within a range of 1.0 to 5 hours fromthe time of ingestion of the medicament;

(iii) ingestible medicaments that are absorbed in both the stomach andthe small intestine have an estimated absorption time within a range of0.5 to 5 hours from the time of ingestion of the medicament;

(iv) ingestible medicaments that are absorbed in the large intestinehave an estimated absorption time of at least 4 hours, and moretypically, within a range of 4 to 30 hours, 6 to 30 hours, 6 to 20hours, or 8 to 20 hours from the time of ingestion of the medicament.

The location within the GI tract at which the particular ingestiblemedicament is absorbed to the bloodstream may often be public knowledge.This location may be provided by, or known to, the manufacturer and/ordistributor of the particular ingestible medicament. Alternatively oradditionally, the location may be known to relevant medicalpractitioners, including doctors and pharmacists, and more particularly,to a medical practitioner of the subject.

For the purpose of this application, an actual absorption time may bedetermined from clinical data, in vivo or in vitro, according toaccepted clinical procedures known to those of skill in the art. Sinceactual absorption is achieved over a period of time, the “actualabsorption time” or “actual absorption time period” may be defined bythe time period at which between 20% and 80% of the absorption occurs.In the absence of such data, the “actual absorption time” or “actualabsorption time period” may be defined by determining the “peak” actualabsorption time, and building a time period of up to 1 hour on each sideof the peak time.

For the purpose of this application, the term “Parkinsonism” is meant toinclude Parkinson's disease, or symptoms of neurodegeneration associatedtherewith.

For the purpose of this application, the term “Parkinsonism” is meant toinclude progressive supranuclear palsy, or symptoms of neurodegenerationassociated therewith.

For the purpose of this application, the term “Parkinsonism” is meant toinclude corticobasal degeneration, or symptoms of neurodegenerationassociated therewith.

For the purpose of this application, the term “Parkinsonism” is meant toinclude multiple system atrophy, or symptoms of neurodegenerationassociated therewith.

For the purpose of this application, the term “Parkinsonism” is meant toinclude Parkinson-plus syndromes (also known as disorders of multiplesystem degeneration), or symptoms of neurodegeneration associatedtherewith.

For the purpose of this application, the term “Parkinsonism” is meant toinclude any neurodegenerative disease in which the subject exhibits atleast one (and typically at least two or three) of the classicalfeatures of Parkinson's disease: tremor, postural instability, andakinesia or bradykesia.

For the purpose of this application, the term “Parkinsonism” is meant toinclude any neurodegenerative disease in which the subject positivelyresponds to a dopaminergic treatment.

For the purpose of this application, the term “Parkinsonism” is meant toinclude any neurodegenerative disease in which the particular subjectpositively responds to an anticholinergic treatment.

For the purpose of this application, the term “Parkinsonism” is meant toinclude any neurodegenerative disease in which a dopaminergic treatmentis clinically utilized to treat the sufferers or subjects.

For the purpose of this application, the term “Parkinsonism” is meant toinclude any neurodegenerative disease in which an anticholinergictreatment is clinically utilized to treat the sufferers or subjects.

For the purpose of this application, the term “Parkinson's disease” (PD)is meant as used by those of skill in the art of neurodegenerativediseases. It is believed that PD is due to the loss of brain cells thatproduce dopamine. Early signs and symptoms of Parkinson's diseaseinclude at least one of tremors (or trembling), slowness of movement,body rigidity and stiffness, and gait problems.

For the purpose of this application, the term “treatment ofParkinsonism” and the like refers to at least one of: (i) delaying onsetof Parkinsonism (e.g., PD); (ii) mitigating the development ofParkinsonism (e.g., PD); and (iii) managing a condition of Parkinsonism(e.g., PD).

For the purpose of this application, the term “managing a condition of”,with respect to Parkinsonism and the like, is meant to include, interalia, improving absorption of a medicament, such as a medicament used inthe treatment of Parkinsonism (e.g., levodopa), into the bloodstream.Such condition management may be manifested by at least one of (i)improved medicament efficacy due to the increased absorption; and (ii)reduced dosage of the medicament, due to the increased medicamentabsorption efficacy.

Referring now to the drawings, FIG. 1 is a schematic block diagram of agastrointestinal treatment system 100 including a vibrating ingestiblecapsule 101 according to an embodiment of the present invention.

As seen in FIG. 1, gastrointestinal treatment system 100 includesvibrating ingestible capsule 101. Capsule 101 includes a capsule housingor shell 102, arranged along a longitudinal axis 103 and having disposedtherein a vibrating agitation mechanism 104. A control mechanism 106,which may for example be, or include, a processor, is adapted to controloperation of vibrating agitation mechanism 104, and at least one powersource 108 provides power to vibrating agitation mechanism 104 andcontrol mechanism 106.

Power source 108 may be any suitable power source, such as one or morealkaline or silver oxide batteries, primary batteries, rechargeablebatteries, capacitors and/or supercapacitors.

Intermittently activated vibrating agitation mechanism 104 is adapted tohave a vibration mode of operation (also termed the first mode ofoperation) and a rest mode of operation (also termed the second mode ofoperation). In the vibration mode of operation, intermittently activatedvibrating agitation mechanism 104 is adapted to exert forces on capsulehousing 102, such that capsule housing 102 exerts vibrations on anenvironment surrounding capsule 101.

In some embodiments, the capsule is in an inoperative state, until thereceipt of an activation input, which causes control mechanism 106 totransition the capsule from the inoperative state to an operative state.

In some embodiments, control mechanism 106 is functionally associatedwith, or includes, a timing mechanism 110, powered by power source 108and adapted to track at least one time characteristic, such as aduration that has passed since an activation input was received, or aduration that has passed since the subject ingested capsule 101.

In some embodiments, capsule 101 is devoid of any sensors for sensing anenvironment thereof. In some such embodiments, control mechanism 106 isadapted, in response to receipt of an activation input, to wait apredetermined delay time, and following the predetermined delay time, toactivate vibrating agitation mechanism 104 to operate in said firstvibration mode of operation.

In other embodiments, such as the embodiment illustrated in FIG. 1,capsule 101 further includes at least one sensor 112, functionallyassociated with control mechanism 106. The at least one sensor 112 maybe adapted to sense at least one parameter within capsule 101 or in anenvironment of capsule 101, and may include a temperature sensor, anillumination sensor, a moisture sensor, a pressure sensor, anaccelerometer, or any other suitable sensor. In some embodiments, the atleast one sensor 112 is adapted to identify a specific condition incapsule 101 or in the vicinity thereof, and to provide an activationinput to control mechanism 106 in response to identification of thecondition. For example, in some embodiments the condition is indicativeof the subject ingesting capsule 101.

For example, in some embodiments sensor 112 may include an illuminationsensor, adapted to identify transition of capsule 101 from anilluminated environment (e.g. outside the human body) to a darkenvironment (e.g. within the human body) and to provide an activationinput in response to identification of such a transition.

As another example, in some embodiments sensor 112 may include a motionor acceleration sensor, such as an accelerometer, adapted to identify anactivation motion carried out by a user on capsule 101 and to provide anactivation input in response to identification of such a transition. Anexample of an accelerometer providing an activation input for agastrointestinal capsule is provided in U.S. patent application Ser. No.15/168,065, filed on May 29, 2016, which is incorporated by referencefor all purposes as if fully set forth herein.

As another example, in some embodiments sensor 112 may include apressure sensor adapted identify pressure applied to the capsule 101,which pressure is indicative of the capsule moving through a pharynx ofthe subject, and to provide an activation input in response toidentification of such pressure.

As a further example, in some embodiments sensor 112 may include atemperature sensor adapted to identify transition of capsule 101 from anarea with ambient temperature (e.g. outside the human body) to an areawith a human body temperature and to provide an activation input inresponse to identification of such a transition.

As another example, in some embodiments sensor 112 may include a motionor acceleration sensor, such as an accelerometer, adapted to identify anactivation motion carried out by a user on capsule 101 and to provide anactivation input in response to identification of such a transition.

As a further example, in some embodiments sensor 112 may include amoisture sensor adapted to identify transition of capsule 101 from a dryarea (e.g. outside the human body) to a moist area (e.g. within thehuman body) and to provide an activation input in response toidentification of such a transition.

In some embodiments, system 100 further includes a control unit 120,which may be remote from capsule 101, and which is adapted to provideone or more inputs to the capsule. In some such embodiments, capsule 101further includes a remote input receiving mechanism 116, functionallyassociated with control mechanism 106, and adapted to receive inputsfrom an input providing mechanism 122 of control unit 120.

In some embodiments, control unit 120 may further include a timingmechanism 126, adapted to track at least one time characteristic, suchas a duration that has passed since a control instruction was providedto capsule 101.

In some embodiments, control unit 120 may further include a user inputreceiver 128, such as a keyboard, touch screen, or touch pad, adapted toreceive input from a user, such as the subject, a medical professionaltreating the subject, or a caregiver of the subject.

Control unit 120 may be any suitable type of control unit. In someembodiments, control unit may be a suitably configured smart phone or atablet computer.

In some such embodiments, control unit 120 may provide inputs to capsule101 by remotely transmitting the inputs from input providing mechanism122 to remote input receiving mechanism 116, for example using a shortrange wireless communication method, such as radio frequency (RF)communication or Bluetooth® communication. One example of such amechanism for providing input to a capsule is described in U.S. patentapplication Ser. No. 15/132,039 filed Apr. 18, 2016 and entitled “INVIVO DEVICE AND METHOD OF USING THE SAME”, which is incorporated byreference for all purposes as if fully set forth herein.

In some embodiments, control unit 120 is adapted to provide theactivation input to control mechanism 106 of capsule 101. In some suchembodiments, control unit 120 provides the activation input prior to thesubject ingesting capsule 101, whereas in other embodiments control unit120 provides the activation input following ingestion of capsule 101 bythe subject.

Relating to the characteristics of vibrating agitation mechanism 104,the vibrating agitation mechanism may be any suitable mechanism that canbe intermittently activated and can apply suitable forces onto capsulehousing 102.

In some embodiments, intermittently activated vibrating agitationmechanism 104 may include a radial agitation mechanism adapted to exertradial forces on capsule housing 102, in a radial direction with respectto the longitudinal axis of housing 102. For example, the radialagitation mechanism may include an unbalanced weight attached to a shaftof an electric motor powered by said battery, substantially as describedin U.S. Pat. No. 9,707,150, which is incorporated by reference for allpurposes as if fully set forth herein.

In some embodiments, intermittently activated vibrating agitationmechanism 104 may include an axial agitation mechanism adapted to exertradial forces on the capsule housing 102, in an axial direction withrespect to a longitudinal axis of housing 102. For example, the axialagitation mechanism may include an electric motor powered by the batteryand an urging mechanism, associated with, and driven by, the electricmotor, such that the urging mechanism adapted to exert said axialforces, substantially as described in U.S. Pat. No. 9,707,150. In someembodiments, the urging mechanism adapted to exert the axial forces inopposite directions. In some embodiments, the urging mechanism isadapted to deliver at least a portion of the axial forces in a knockingmode.

In some embodiments, the forces exerted by intermittently activatedvibrating agitation mechanism 104 on capsule housing 102 in thevibration mode of operation include radial forces in a radial directionwith respect to the longitudinal axis of the housing and axial forces inan axial direction with respect to the longitudinal axis. In someembodiments, a single agitation mechanism exerts both the radial and theaxial forces. In other embodiments, the axial forces are exerted by oneagitation mechanism, and the radial forces are exerted by another,separate, agitation mechanism, where both agitation mechanisms form partof intermittently activated vibrating agitation mechanism 104.

In some embodiments, the intermittently activated vibrating agitationmechanism 104 may include a magnet mounted onto a rotor adapted to exerta magnetic field as well as radial forces on capsule housing 102. Forexample, such a magnetic vibration agitation mechanism is described inU.S. patent application Ser. No. 15/058,216 filed on Mar. 2, 2016 andentitled “PHYSIOTHERAPY DEVICE AND METHOD FOR CONTROLLING THEPHYSIOTHERAPY DEVICE”, which is incorporated by reference for allpurposes as if fully set forth herein.

In some embodiments, housing 102 may include first and second members,and vibrating agitation mechanism 104 may include a mechanism adapted toeffect a vibration by moving the first member of the housing in theopposite direction relative to the second member of the housing,substantially as described in U.S. Pat. No. 9,078,799, which isincorporated by reference for all purposes as if fully set forth herein.

In some embodiments, housing 102 may include a vibration agitationmechanism 104 which makes use of a pendulum to cause vibration in thevicinity of the capsule, for example as described in CN PatentApplication Number 105997466 filed on Jun. 16, 2016 and entitled“INTELLIGENT VIBRATING ELECTRONIC CAPSULE”, which is incorporated byreference for all purposes as if fully set forth herein.

In the vibrating mode of operation, intermittently activated vibratingagitation mechanism 104 is adapted to have a plurality of vibrationcycles, where each cycle includes a vibration duration followed by arepose duration. Forces are exerted by the vibrating agitation mechanism104 on capsule housing 102 only during the vibration duration, and assuch capsule housing 102 only exerts forces on an environment thereofduring the vibration duration.

In some embodiments, the number of vibration cycles per hour is in therange of 20 to 400, 40 to 400, 60 to 400, 80 to 400, 40 to 380, 60 to380, 80 to 380, 40 to 360, 60 to 360, 80 to 360, 100 to 360, 100 to 330,100 to 300, 100 to 280, 100 to 250, 100 to 220, 100 to 200, 120 to 300,120 to 280, 120 to 250, 120 to 220, 120 to 200, 150 to 300, 150 to 280,150 to 250, 150 to 220, 150 to 200, 170 to 300, 170 to 250, 170 to 220,or 170 to 200.

In some embodiments, the repose duration is greater than the vibrationduration. In some embodiments, the vibration duration is in the range of0.1 second to 10 seconds, 1 second to 10 seconds, 1 second to 9 seconds,2 seconds to 9 seconds, 3 seconds to 9 seconds, 3 seconds to 8 seconds,3 seconds to 7 seconds, 3 seconds to 6 seconds, or 4 seconds to 6seconds.

In some embodiments, the repose duration is in the range of 1 second to180 seconds, 3 seconds to 180 seconds, 5 seconds to 180 seconds, 5seconds to 150 seconds, 5 seconds to 120 seconds, 8 seconds to 100seconds, 8 seconds to 30 seconds, 10 seconds to 80 seconds, 10 secondsto 70 seconds, 10 seconds to 60 seconds, 10 seconds to 50 seconds, 10seconds to 40 seconds, 10 seconds to 30 seconds, 10 seconds to 20seconds, or 15 seconds to 20 seconds.

In some embodiments, the total duration of one vibration cycle is in therange of 1.1 seconds to 200 seconds, 5 seconds to 200 seconds, 10seconds to 200 seconds, 10 seconds to 150 seconds, 10 seconds to 100seconds, 10 seconds to 80 seconds, 10 seconds to 50 seconds, 10 secondsto 40 seconds, 10 seconds to 30 seconds, 15 seconds to 50 seconds, 15seconds to 40 seconds, 15 seconds to 30 seconds, or 15 seconds to 25seconds.

In some embodiments, the cumulative duration of the vibrating mode ofoperation, or the cumulative duration during which vibration cycles areoccurring, is in the range of 1 hour to 12 hours, 2 hours to 10 hours, 2hours to 8 hours, 2 hours to 6 hours, 2 hours to 4 hours, or 2 hours to3 hours. It will be appreciated that the cumulative duration ofvibration cycles may be dependent on properties of power source 108.

It will be appreciated by persons skilled in the art that the vibrationmode of operation may be intermittent, or interrupted, such thatvibrating agitation mechanism 104 is operative in the vibration mode fora first duration, for example 30 minutes, then does have any vibrationcycles for a second duration, for example 1 hour, and then is operativein the vibration mode and has vibration cycles for a third duration, forexample two hours. The cumulative duration relates to the sum of alldurations during which vibrating agitation mechanism 104 was operativein the vibration mode and included vibration cycles, including thevibration duration and the repose duration of the vibration cycle.

In some embodiments, vibrating agitation mechanism 104 is configured toexert forces on the capsule housing 102, such that a net force exertedby the capsule housing 102 on the environment thereof is in the range of50 grams force (gf) to 600 gf, 50 gf to 550 gf, 100 gf to 550 gf, 100 gfto 500 gf, 150 gf to 500 gf, 200 gf to 500 gf, or 200 gf to 450 gf.

In some embodiments, vibrating agitation mechanism 104 is configured toexert said forces on capsule housing 102 to attain a capsule housing 102vibrational frequency within a range of 10 Hz to 650 Hz, 15 Hz to 600Hz, 20 Hz to 550 Hz, 30 Hz to 550 Hz, 50 Hz to 500 Hz, 70 Hz to 500 Hz,100 Hz to 500 Hz, 130 Hz to 500 Hz, or 150 Hz to 500 Hz.

It will be appreciated that the exact specifications of the capsule,such as the specific frequency and force ranges applicable to a specificcapsule, are dependent on the specifications of the power source and ofthe vibrating agitation mechanism.

It will be further appreciated that a specific capsule may be controlledby the control mechanism such that different vibrational frequencies maybe attained and/or different net forces may be exerted, by the capsulein different vibration cycles of the capsule. Due to the naturaldistinction between subjects, use of multiple different parameters indifferent vibration cycles of a single capsule would allow the capsuleto successfully treat multiple subjects, even if the personal optimaltreatment for those subjects is not the same, as there is a higherchance that in at least some of the vibration cycles the activationparameters of the capsule would reach, or be close to, the optimalparameters for each specific subject.

Control mechanism 106 is adapted to control the operation ofintermittently activated vibrating agitation mechanism 104. Such controlmay include control of any one or more of the force applied by thevibrating agitation mechanism, the vibrational frequency reached, thetimes in which vibrating agitation mechanism 104 operates in thevibration mode of operation, the vibration duration of each vibrationcycle, the repose duration of each vibration cycle, the vibration cycleduration, and cumulative vibration duration of the vibrating agitationmechanisms.

In some embodiments, control mechanism 106 is adapted to receiveinformation relating to the desired vibration protocol from control unit120, prior to ingestion of the capsule or to activation thereof, orduring the capsule's traversal of the subject's GI tract. For example,the information may be remotely transmitted from control unit 120 tocontrol mechanism 106, for example using a short range wirelesscommunication method. In some embodiments, the information istransmitted as a list of vibration parameters for effecting thevibration protocol. In some embodiments, the information is transmittedas executable code for effecting the first vibration protocol.

In some embodiments, the information includes a desired number ofvibration cycles, a desired vibration duration in each vibration cycle,a desired repose duration in each vibration cycle, a desired cumulativevibration duration, and the like.

Control mechanism 106 may be adapted to control vibrating agitationmechanism 104 so that the capsule applies forces to an environmentthereof, such that within the gastrointestinal tract, a mechanicalstimulation of the wall of the gastrointestinal tract is effected.

Reference is now additionally made to FIG. 2, which is a schematicflowchart of a method for using a vibrating gastrointestinal capsule toimprove or accelerate the absorption into the bloodstream of amedicament for treatment of Parkinsonism, and/or to improve the efficacyof such a medicament, according to the present invention. The method maybe based on the use of a gastrointestinal capsule system including (orconsisting of) a vibrating ingestible capsule, such as capsule 101 ofsystem 100 of FIG. 1.

As seen at step 200, vibrating gastrointestinal capsule is provided. Thevibrating gastrointestinal capsule may have, as described with respectto FIG. 1, a housing; a vibrating agitation mechanism adapted such that,in a first vibrating mode (“vibration mode”) of operation, the housingexerts vibrations on an environment surrounding the vibratinggastrointestinal capsule; and a power supply disposed within the housingand adapted to power the vibrating agitation mechanism. Typically, thecapsule includes an on-board control mechanism adapted to control oractivate the vibrating agitation mechanism. The control mechanism mayform a component of such a vibrating agitation mechanism.

At step 204, an ingestible medicament for treatment of Parkinsonism isingested by the subject.

The ingestible medicament for treatment of Parkinsonism may include anyone or more of levodopa; at least one dopaminergic agent; at least onecatecholamine precursor; a dopamine precursor; at least one dopamineprecursor agent, such as (L)-3,4-dihydroxyphenylalanine;N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine; tyrosinehydroxylase; apomorphine; at least one anticholinergic agent; at leastone agent selected to antagonize at least one cholinergic receptor; atleast one of benzhexol and orphenadrine; at least one selectiveallosteric potentiator of metabotropic glutamate receptor 4 (mGluR4),such as N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide.

In some embodiments, the ingestible medicament may be ingested directly,for example by ingesting a tablet, capsule, liqui-gel capsule, chewabletablet, syrup, or any other form of dosage including the medicament.

In some embodiments, the ingestible medicament may be ingested within amedicament delivery capsule, adapted to deliver the medicament to aspecific location in the gastrointestinal tract. Examples of suchmedicament delivery capsules are described in:

U.S. Pat. Nos. 5,170,801; 6,632,216; 6,776,165; 6,929,363; 8,202,697;8,518,022; 8,597,278; and 8,771,730;

U.S. Patent Application Publication Numbers 2004/0253304; 2004/0267240;2005/0058701; 2005/0148847; 2008/0275430; 2009/0306633; and2010/0049012; PCT Patent Application Publication Numbers WO2006/025013;WO2008/012700; and WO 2009/063375;

all of which are incorporated by reference for all purposes as if fullyset forth herein. At step 206, the vibrating gastrointestinal capsule isingested by the subject.

While the ingestible medicament and the vibrating gastrointestinalcapsule may be ingested at the same time, or within 0-30 minutes of eachother, no order of action is implied by FIG. 2, and the capsule may beingested prior to the medicament.

In some embodiments, the vibrating gastrointestinal capsule functionsalso as a medicament delivery system for delivery of the ingestiblemedicament and delivers the medicament to a specific area or location inthe gastrointestinal tract of the subject. In such embodiments, thesubject ingests a single capsule, the vibrating ingestible capsule,thereby fulfilling steps 204 and 206 of the method.

As shown, step 208A includes controlling at least one of a time ofingesting the vibrating gastrointestinal capsule and a timing of saidvibration mode of operation (e.g., when the vibration mode is initiated,a duration of the vibration mode, etc.) to at least partially transpirewithin at an absorption time period of the ingestible medicament withinthe gastrointestinal tract of the subject. Typically, the absorptiontime period is an estimated absorption time period, as defined herein.In some cases, an actual absorption time period may be determined,again, as defined herein.

Additionally or alternatively, the method may include controlling atleast one of a timing of ingesting the vibrating gastrointestinalcapsule and a timing of said vibration mode of operation such that thevibration mode at least partially transpires within a particular timeperiod with respect to the ingesting of the ingestible medicament (step208B).

The particular time period may be within 5 hours, within 4 hours, within3.5 hours, within 3 hours, or within 2.5 hours of the ingesting of theingestible medicament, and more typically, within 2 hours, within 1.5hours, within 1 hour, or within 0.5 hours thereof.

In some embodiments, the method may include controlling at least one ofa timing of ingesting the vibrating gastrointestinal capsule and atiming of said vibration mode of operation such that said vibration modeat least partially transpires when the capsule is in a region of thegastrointestinal tract in which the medicament is typically absorbedinto the bloodstream. The region of the gastrointestinal tract mayinclude one or more of the stomach of the subject, the duodenum of thesubject, the small intestine of the subject, the large intestine of thesubject, or the colon of the subject.

For example, when cooperating with the medicament levadopa, which istypically absorbed into the bloodstream through the stomach walls and/orthe small intestine walls, the vibration mode at least partiallytranspires within a time period in which the capsule traverses, or isexpected to traverse, the stomach and small intestine.

In some embodiments, and as described in further detail herein, themethod may include transitioning the capsule (from an inoperative state)to an operative state.

The capsule may be pre-programmed with a vibration protocol. Thisprotocol may include, by way of example, a particular or pre-determinedactivation time following ingestion, in which the capsule istransitioned from an inoperative state to an operative state.

Alternatively or additionally, the capsule may receive an activationinput in an active fashion (e.g., from an external controller via RF) orin a passive fashion (e.g., a signal from a sensor to the on-boardcontroller). It will be appreciated that step 202, in which thevibrating ingestible capsule is transitioned from the inoperative stateto the operative state, may be performed after ingestion of the capsuleby the subject (e.g., in the case of external control via RF).

In some embodiments, control mechanism 106 may optionally receive adesired vibration protocol for the subject, at an optional step 203.

In some embodiments, providing of the predetermined time(s) at step 202and/or providing the desired vibration protocol for the subject at step203 occurs at the time of manufacturing of the capsule, for example bypre-programming the time into the control mechanism.

In some embodiments, providing of the predetermined time(s) at step 202and/or providing the desired vibration protocol for the subject at step203 may be effected by a control unit, such as control unit 120 of FIG.1.

The programming of the vibration protocol may include remotelytransmitting the desired vibration protocol from control unit 120 tocontrol mechanism 106, for example using a short-range wirelesscommunication method. In some embodiments, the desired vibrationprotocol is transmitted as a list of vibration parameters for effectingthe vibration protocol. In some embodiments, the desired vibrationprotocol is transmitted as executable code for effecting the vibrationprotocol.

As discussed hereinabove, in some embodiments the activation input maybe received from the control unit 120 or from sensors within the capsulesensing that the capsule has been ingested or that a user has carriedout an activation motion with the capsule.

Substantially as described hereinabove, the vibrating ingestible capsulemay be activated prior to the user ingesting the capsule at step 206,for example by a signal from the control unit or by the user carryingout an activation motion. In other embodiments, the activation input isprovided at the time of ingestion or immediately thereafter, for exampleby sensors sensing a change in the environment of the capsule due to itsingestion, as described at length hereinabove. In yet other embodiments,the activation input may be provided remotely when the capsule isalready in the body of the subject, for example by remote communicationfrom control module 120.

Following activation of capsule 101, or together therewith, capsule 101is ingested by the subject, and begins to travel through thegastrointestinal tract of the subject, as evident from step 206.

Operation of vibrating agitation mechanism 104 in the vibrating mode ofoperation at step 208A or 208B effects vibration of capsule housing 102,as described hereinabove, such that the housing exerts vibrations on theenvironment surrounding the capsule. Specifically, vibration of capsulehousing 102 may be intended to effect a mechanical stimulation of thewall of the gastrointestinal tract at a time when the ingestedmedicament may be absorbed, thereby to increase or accelerate theabsorption of the ingested medicament into the bloodstream of thesubject, for delivery to a target treatment region of the medicament.

Typically, the target treatment region of medicaments for treatment ofParkinsonism is in or near the brain, and as such the medicament,absorbed to the bloodstream in the gastrointestinal tract, is deliveredto the target treatment region away from the gastrointestinal tract.

A treatment session as defined in FIG. 2 may be repeatedly administeredto the subject as specified in the treatment protocol for the subject.In some embodiments, the treatment protocol includes administering aplurality of treatment sessions to the subject. In some embodiments, thetreatment protocol includes administering at least one treatment sessionto the subject per week, over a treatment period of at least two weeks,at least at least three weeks, at least four weeks, at least five weeks,at least six weeks, or at least eight weeks. In some embodiments, thetreatment protocol includes administering 1 to 7 treatment sessions perweek, 3 to 14 treatment sessions per two weeks, 2 to 7 treatmentsessions per week, 5 to 14 treatment sessions per two weeks, 3 to 7treatment sessions per week, 7 to 14 treatment sessions per two weeks, 4to 7 treatment sessions per week, or 5 to 7 treatment sessions per week.

This patent application claims the benefit of unpublished U.S.Provisional Patent Application No. 62/655,031 filed on Apr. 9, 2018, thespecification, figures, claims and abstract of which are eachincorporated herein by reference in their entireties.

It will be appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, mayalso be provided in combination in a single embodiment. Conversely,various features of the invention, which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable sub-combination. Although the invention has beendescribed in conjunction with specific embodiments thereof, it isevident that many alternatives, modifications and variations will beapparent to those skilled in the art. Accordingly, it is intended toembrace all such alternatives, modifications and variations that fallwithin the spirit and broad scope of the appended claims. Allpublications, patents and previously-published patent applicationsmentioned in this specification are herein incorporated in theirentirety by reference into the specification, to the same extent as ifeach individual publication, patent or previously-published patentapplication was specifically and individually indicated to beincorporated herein by reference. In addition, citation oridentification of any reference in this application shall not beconstrued as an admission that such reference is available as prior artto the present invention.

1. A vibrating ingestible capsule for promoting absorption of aningested medicament into the blood stream, the vibrating ingestiblecapsule including: a housing; a vibrating agitation mechanism adaptedsuch that, in a vibration mode of operation, said housing exertsvibrations on an environment surrounding the vibrating ingestiblecapsule; a power supply disposed within said housing and adapted topower said vibrating agitation mechanism; and a control mechanismadapted to activate said vibrating agitation mechanism to be operativein said vibration mode of operation, said control mechanism adapted tocontrol a timing or activation delay of said vibration mode of operationsuch that said vibration mode of operation at least partially transpireswithin at least one of an estimated absorption time period and an actualabsorption time period of the ingested medicament within thegastrointestinal tract of the subject; wherein, in said vibration modeof operation, said vibrating agitation mechanism is further adapted toeffect at least one of: (a) exert forces on said housing such that a netforce exerted by said housing on said environment is within a range of50 grams force to 600 grams force; (b) exert said forces on said housingsuch that a vibrational frequency of said housing is within a range of10 Hz to 650 Hz.
 2. The vibrating ingestible capsule of claim 1, whereinsaid control mechanism is adapted to activate the vibration agitationmechanism to be operative in said vibration mode of operation inresponse to receipt of an activation input.
 3. The vibrating ingestiblecapsule of claim 1, wherein a cumulative duration of said vibrating modeof operation is within a range of 1 hour to 12 hours. 4-6. (canceled) 7.A method of using a vibrating ingestible capsule in coordination with aningestible medicament for treatment of Parkinsonism, the methodcomprising: (a) providing the vibrating ingestible capsule, the capsuleincluding: a housing; a vibrating agitation mechanism adapted such that,in a vibration mode of operation, said housing exerts vibrations on anenvironment surrounding the vibrating ingestible capsule; a power supplydisposed within said housing and adapted to power said vibratingagitation mechanism; and a control mechanism adapted to activate saidvibrating agitation mechanism to operate in said vibration mode ofoperation; (b) ingesting the ingestible medicament; (c) ingesting thevibrating ingestible capsule; and (d) controlling at least one of a timeof said ingesting of the vibrating ingestible capsule and a timing oractivation delay of said vibration mode of operation, such that saidvibration mode of operation at least partially transpires within atleast one of an estimated absorption time period and an actualabsorption time period of the ingestible medicament within thegastrointestinal tract of the subject.
 8. The method of claim 7, whereinsaid controlling is effected such that said vibration mode of operationat least partially transpires during said actual absorption time.
 9. Themethod of claim 7, wherein said actual absorption time period occurswhen the ingestible medicament is disposed in a small intestine of thesubject.
 10. The method of claim 7, wherein said controlling of iseffected such that said vibration mode of operation at least partiallytranspires during said estimated absorption time.
 11. The method ofclaim 10, wherein said estimated absorption time is within a range of0.5 to 5 hours from said ingesting of said ingestible medicament. 12.The method of claim 7, wherein said ingesting of said vibratingingestible capsule occurs after said ingesting of said ingestiblemedicament, and transpires within 4 hours of said ingesting of theingestible medicament.
 13. The method of claim 7, wherein said ingestingof said vibrating ingestible capsule is simultaneous with said ingestingof the ingestible medicament.
 14. The method of claim 7, furthercomprising timing said vibration mode of operation to at least partiallytranspire within 5 hours, within 4 hours, within 3.5 hours, within 3hours, within 2.5 hours, within 2 hours, within 1.5 hours, within 1hour, or within 0.5 hours of said ingesting of the ingestiblemedicament.
 15. The method of claim 7, wherein the ingestible medicamentfor treatment of Parkinsonism includes at least one of: levodopa; atleast one dopaminergic agent; at least one catecholamine precursor; adopamine precursor;N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine; tyrosinehydroxylase; apomorphine; at least one anticholinergic agent; at leastone agent selected to antagonize at least one cholinergic receptor; atleast one of benzhexol and orphenadrine; at least one selectiveallosteric potentiator of metabotropic glutamate receptor 4 (mGluR4);N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide.
 16. Themethod of claim 15, wherein the medicament for treatment of Parkinsonismis adapted to delay an onset of Parkinsonism.
 17. The method of claim15, wherein the medicament for treatment of Parkinsonism is adapted tomitigate or retard a development of Parkinsonism.
 18. The method ofclaim 15, wherein the medicament for treatment of Parkinsonism isadapted to manage a condition of Parkinsonism.
 19. The method of claim7, wherein said vibration mode of operation at least partiallytranspiring within at least one of an estimated absorption time periodand an actual absorption time period of the ingestible medicament withinthe gastrointestinal tract of the subject effects an increasedabsorption of the ingestible medicament for treatment of Parkinsonism,thereby providing at least one of the following impacts: improving atherapeutic efficacy of the medicament; and enabling the use of a lowerdosage of said medicament than a dosage used without use of saidvibrating ingestible capsule, without impairing or diminishingtherapeutic efficacy.
 20. The method of claim 7, wherein said vibrationmode of operation is effected within the gastrointestinal tract so as toachieve at least one of the following results: stimulate the entericnervous system of the subject; induce at least one peristaltic wave in awall of the gastrointestinal tract; and effect increasing peristalsis ina wall of the gastrointestinal tract.
 21. The method of claim 7,wherein, in said vibration mode of operation, said vibrating agitationmechanism is further adapted to effect at least one of: (a) exert forceson said housing such that a net force exerted by said housing on saidenvironment is within a range of 50 grams force to 600 grams force; (b)exert said forces on said housing such that a vibrational frequency ofsaid housing is within a range of 10 Hz to 650 Hz.
 22. An arrangementcomprising: (a) the vibrating ingestible capsule of claim 1; and (b) aningestible medicament for treatment of Parkinsonism.
 23. The arrangementof claim 22, wherein the ingestible medicament for treatment ofParkinsonism includes at least one of: levodopa; at least onedopaminergic agent; at least one catecholamine precursor; a dopamineprecursor; N-methyl-N-(2-propynyl)-2-methyl-1-phenylethyl-2-amine;tyrosine hydroxylase; apomorphine; at least one anticholinergic agent;at least one agent selected to antagonize at least one cholinergicreceptor; at least one of benzhexol and orphenadrine; at least oneselective allosteric potentiator of metabotropic glutamate receptor 4(mGluR4); N-phenyl-7-(hydroxylimino)cyclopropa[b]chromen-1a-carboxamide.